Submissions for variant NM_000143.4(FH):c.194A>G (p.Asp65Gly)

gnomAD frequency: 0.00001  dbSNP: rs145116688

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197441	SCV000251439	likely pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Observed in an individual with uterine leiomyomas, a cohort of healthy adult individuals, and a control individual (PMID: 31746132, 34404389, 29641532); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34404389, 29641532, 31746132)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197441	SCV000544280	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 65 of the FH protein (p.Asp65Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs145116688, gnomAD 0.002%). This missense change has been observed in individual(s) with fumarate hydratase deficiency (PMID: 31746132). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214390). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FH protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 31746132). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001013787	SCV001174416	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	The p.D65G variant (also known as c.194A>G), located in coding exon 2 of the FH gene, results from an A to G substitution at nucleotide position 194. The aspartic acid at codon 65 is replaced by glycine, an amino acid with similar properties. This alteration was identified in a compound heterozygous state with FH c.1293delA in a patient with fumarate hydratase (FH) deficiency (Grocott O et al. Am. J. Med. Genet. A, 2019 Nov). This alteration is predicted to be deleterious by in silico protein analysis. Functional studies on the protein effect demonstrate only a minor effect in enzyme kinetics relative to wildtype (Grocott O et al. Am. J. Med. Genet. A, 2019 Nov). This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this alteration is classified as a disease-causing mutation in association with autosomal recessive FH deficiency when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with HLRCC is unlikely.
Sema4, Sema4	RCV001013787	SCV002535548	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation
Baylor Genetics	RCV000456662	SCV004197300	likely pathogenic	Fumarase deficiency	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000456662	SCV002605168	pathogenic	Fumarase deficiency	2022-11-18	no assertion criteria provided	literature only